1. Field of the Invention
This invention relates generally to the field of cell adhesion and more specifically to integrins and their RGD-binding domains.
2. Background Information
Many cell-cell and cell-matrix interactions depend upon the engagement of specific ligands by members of the integrin family of cell-adhesion receptors. Integrins are heterodimeric transmembrane receptors whose ligand-binding specificity is determined by the combination of .alpha. and .beta. subunits. Of associations between the nine known .beta. subunits and 17 known .alpha. subunits, integrins .alpha..sub.5 .beta..sub.1, .alpha..sub.IIb .beta..sub.3 and all or most .alpha..sub.v -containing integrins, but generally not others, recognize an arginine-glycine-aspartic acid (RGD) motif. Ligands for these RGD-binding integrins include a variety of extracellular matrix proteins such as fibronectin, vitronectin, osteopontin and collagens; plasma proteins such as fibrinogen and von Willebrand factor; cellular counter-receptors; the disintegrins; and viral proteins.
Integrins are fundamental to processes of physical adhesion involving cell-cell or cell-matrix interactions and also can mediate signal transduction through their cytoplasmic domains. RGD-binding integrins function in biological processes including cell migration in development, wound healing and tissue repair, platelet aggregation and immune cell recognition. A role for these integrins also is implicated in a variety of pathologies including thrombosis, osteoporosis, tumor growth and metastasis, inflammation and diseases of viral etiology such as acquired immune deficiency syndrome. The physiological relevance of integrins is underscored by the observation that hereditary mutations can destroy RGD-binding activity and have pathological consequences resulting in, for example, the bleeding disorder, Glanzmann's thrombasthenia.
Peptides and protein fragments can be used to modulate the activities of RGD-binding integrins. One class of peptides that can act as competitors of RGD-binding activity includes peptides that contain the RGD motif or a functional equivalent of this motif. A second class of peptides includes those peptides that bind RGD-containing ligands through structures that function similarly to the integrin domain that contacts the RGD sequence. Peptides that structurally mimic the RGD-binding site in integrin .beta. subunits, for example, can modulate the activity of RGD-binding integrins.
Peptides that specifically bind ligands of RGD-binding integrins would be useful for modulating the cell aggregation and cell adhesion that occur in various pathological conditions including, for example, thrombosis, osteoporosis, inflammation, metastasis, wound healing and graft rejection. However, few such peptides have been described. Thus, there is a need for peptides that effectively and selectively modulate the activity of RGD-binding integrins. The present invention satisfies this need by providing novel cyclic peptides having specific RGD-binding activity and provides related advantages as well.